Multidisciplinary Approaches to The FLASH Radiotherapy

Radiotherapy (RT) is extensively used in cancer treatment, although its toxicity often limits the treatment of radioresistant tumors. In this context, it has been recently shown, that irradiation at ultra-high dose rate (UHDR) (mean dose rate ≥40 Gy/s, with specific beam characteristics), called “FLASH-RT” may significantly reduce radiation-induced toxicity on normal tissues, while keeping similar antitumor effect as conventional RT [1]. This so called “FLASH effect” has been demonstrated in vivo on different animal models and various tumor types, using different radiations types (electrons, protons, carbon ions, and photons [2]) and pulse structures. While these rapidly accumulating results indicate bright prospects, the clinical translation is still in its early phase, due to different challenges. First, several technological issues must be addressed to design new stable radiation sources capable of delivering beams with fluences orders of magnitude higher than those of conventional RT, and with a reliable real time beam monitoring system. This also implies the need of new dosimetric protocols, since most of the active dosimeters used for conventional beams do not respond accurately to UHDR and ultra high dose-per-pulse (UHDP) [3, 4]. Accurate dosimetry is not only needed for clinical implementation, but also for more robust and reproducible pre-clinical experiments [5]. The second challenge is understanding the biological mechanism underlying the FLASH effect, to explain the differential response of cancer vs. normal tissues. Several hypotheses have been considered, involving the whole cascade from the early radiation chemistry events to the classical radiation-induced molecular and cellular mechanisms and tissue recovery processes, also including a role for (epi)-genetics, stem cells or the immune system. While many results support different hypotheses, no compelling evidence exists that can yet confirm any of them.